JP4425093B2 - Method for treating pain by administration of a 24-hour oral opioid preparation with a rapid initial rate of increase in drug level in plasma - Google Patents

Abstract

Oral sustained release opioid formulation comprises: an opioid analgesic, a retardant material to cause the opioid analgesic to be released at a rate to provide an analgesic effect after oral admin. to a human patient for 24 hrs, the formulation when administered in humans providing an initially rapid rate of rise in the plasma conc. of the opioid characterised by providing an absorption half-life of 1-8 hrs. in the fastened state. Method for titrating human patients with a sustained release oral opioid formulation comprises: 1) administering to a human patient on a once-a-day basis a unit dose of an oral sustained release formulation comprising a dose of an opioid analgesic and a retardant material as described above, 2) monitoring pharmacokinetic and pharmacodynamic parameters elicited by the formulation in the human patient and determining whether the pharmacokinetic and/or pharmacodynamic parameters are appropriate to treat the patient on a repeated basis, 3) titrating t he patient by adjusting the dose of the opioid analgesic administered to the patient by administering a unit dose of the sustained release opioid analgesic formulation if it is determined that the pharmacokinetic and/or the pharmacodynamic parameters are not satisfactory or maintaining the dose of the opioid analgesic in the unit dose at a previously administered amt. if the pharmacokinetic and/or pharmacodynamic parameters are deemed appropriate, 4) continuing the step 3 titration by adjusting the dose of the opioid analgesic until appropriate steady state pharmacokinetic and/or pharmacodynamic parameters are achieved in the patient, and 5) continuing the admin. of the dose of the opioid analgesic in the oral sustained release formulation on a once-a-day basis until treatment is terminated.

Description

  The present invention relates to a sustained-release drug capable of bioavailability of an analgesic agent, particularly an opioid analgesic agent, and relates to a preparation having a prolonged effect when administered orally.

  All sustained release formulations are intended to extend the duration of the pharmacological response after administration of the drug beyond that normally experienced after administration of the rapid release dosage. This prolonged response period provides many inherent therapeutic benefits that are not achievable with corresponding short-acting immediate release formulations. This is especially true in the treatment of cancer patients or other patients who need treatment to relieve severe pain. This is because in this case the blood level of the opioid analgesic must be maintained at a therapeutically effective value in order to eliminate pain. In order to maintain an effective and stable blood level of a drug, conventional rapid-acting medications must be used frequently and carefully, due to rapid absorption and excretion of the compound and inactivation by metabolism As a result, the blood level of the active drug varies, which causes a serious problem in maintaining the analgesic effect.

  Prior art reports relating to the production and use of compositions that provide sustained release of active compounds from carriers basically relate to the release of active substances into the physiological fluids of the gastrointestinal tract. However, it is generally recognized that the presence of an active substance simply in the gastrointestinal fluid does not provide confirmation of bioavailability.

  In order to be absorbed, the active medicinal substance must be in solution. The time required for an active substance to dissolve at a given ratio from one unit of dosage is released from one unit of dosage within a specified reference time by a test method carried out under standardized conditions. Determined by the ratio of the amount of active medicinal substance. The physiological fluid in the gastrointestinal tract is the medium in determining the dissolution time. In the current state of the art, many good test procedures for measuring dissolution times for pharmaceutical compositions are accepted and these test procedures are described in pharmacopoeia commentary around the world.

  The basic principle in guiding the use of opioid analgesics in the treatment of chronic pain is the individualization of doses, which vary between individual patients and vary within the same patient, tailored to the opioid requirements. . Pain specialists emphasize the importance of titration. This large patient-specific difference in each patient's response to a dose of opioid makes it necessary to determine the appropriate dose for a particular patient. Many factors contribute to patient-specific differences in response to opioid analgesics, but one important factor is based on large patient-specific variations in metabolism and pharmacokinetics.

  The opioids that are most effectively dosed are long (12-72 hours) and compared to analgesics with a more variable half-life (eg methadone, levorphanol) Those with a relatively short elimination half-life of 3-5 hours (eg, morphine, hydromorphone, oxycodone). The shorter half-life drug reaches a steady state concentration in about one day, rather than a few days to a week or more. Only at steady state can one expect to maintain a balance between efficacy and side effects on a given dosing schedule. If it is certain that the patient will be in a roughly steady state about one day after the start of administration, it can be assessed much more quickly whether the dose is appropriate in this case.

  In the industry, once-daily oral dosage agents have been developed and marketed. However, at present, no 24-hour sustained release opioid analgesic is commercially available. However, immediate release opioid analgesic administration, such as parenteral formulations, immediate release solutions or tablets, etc., to determine the appropriate dose for patients seeking opioid analgesic treatment based on their experience with 12 hour sustained release formulations A general perception in the medical community has led to the need to use drugs. By using an immediate release opioid formulation, the patient can be transferred to a sustained release oral opioid formulation only after the patient has reached a suitable steady state value.

  Thus, for general practitioners, a suitable pharmacokinetic index (e.g., absorption) for use in both determining the dosage of a patient receiving opioid analgesic treatment with the same dosage and for long-term maintenance treatment after determining the dosage of this patient. It would be highly desirable to have a sustained release opioid analgesic formulation that provides the properties) and associated patient pharmacodynamic response (eg, pain relief). This eliminates the need for the patient to first determine an appropriate amount of immediate release opioid dosage before moving to a sustained release dosage for long-term treatment, as described above. Preferably, the sustained release formulation has a duration of efficacy greater than about 12 hours so that the drug administered to the patient is only once a day. Preferably, the sustained-release dosage not only provides pain relief for a period of about 12 hours or longer, but in addition, it can be used to determine the appropriate dosage of the same sustained-release dosage for patients receiving opioid analgesia. Those that provide pharmacokinetic and pharmacodynamic properties that may also be used for long-term treatment are preferred.

  Many of the currently available oral opioid analgesic formulations must be administered every 4-6 hours daily. Only a few are limited and are formulated for less frequent 12-hour administration.

  In addition, a drug formulation that provides an absorption characteristic suitable for determining an appropriate amount of a patient who is going to receive opioid analgesic treatment and that continuously releases sufficient opioid analgesic to provide analgesia for at least 12 hours. Need to develop. This eliminates the need for the patient to first determine the appropriate amount of an immediate release dosage of the opioid analgesic (eg, parenteral, oral, rectal) and then transfer the patient to a sustained release formulation of the opioid analgesic.

Morphine, the prototypical opioid analgesic, is formulated into a twice daily controlled release agent (ie, MS Contin® tablets, commercially available from Purdue Frederic Company; and FHFaulding and Kapanol®, commercially available from the Company; and Oramorph® SR, previously referred to as Roxanol® SR, commercially available from Roxane.

  An opioid preparation for oral administration having a prolonged analgesic action without increasing the adverse effect rate is highly desired. Such oral sustained release formulations of opioid analgesics are bioavailable and are effective drug drugs that provide an analgesic duration of about 24 hours or longer when administered orally. A steady state of blood level (eg plasma level) can be obtained.

Accordingly, it is an object of the present invention to provide a method for palliative treatment of severe pain in a patient with an orally administered opioid analgesic suitable for once daily administration.

  Yet another object of the present invention is to provide a method for treating a patient with a once-daily opioid analgesic formulation that provides an analgesic effect beyond that obtained with a suitable Q12H (every 12 hour) analgesic treatment. is there.

  Yet another object of the present invention is to provide an opioid analgesic agent that can be used to continually release opioids and at the same time determine the appropriate amount for patients receiving opioid analgesic treatment.

  With these and other objectives in mind, the present invention provides a minimum analgesic concentration in many patients with pain that can be measured at the time of administration, if not intensely, in order to provide a 24-hour administration of opioid analgesics. Partly related to the surprising discovery that it is important to create a sustained-release formulation for pain using an analgesic that releases opioids quickly and quickly to reach quickly . Opioid formulation for sustained release once a day for oral administration using a single dosage form of the present invention to determine the appropriate dose for patients receiving opioid analgesia due to the unique release characteristics of the dosage form of the present invention Can be sustained release of opioid analgesics. The formulation includes an opioid analgesic and an effective amount of at least one lagging agent that releases the opioid analgesic at a rate effective to provide an analgesic effect for at least about 24 hours after oral administration to a human patient.

  The formulations of the present invention rapidly and rapidly increase the plasma concentration of opioids characterized by an absorption half-life of 1.5 to about 8 hours when administered to humans. In a preferred embodiment, the once-daily oral sustained release formulation of the present invention exhibits an absorption half-life of 2 to about 4 hours.

  The present invention is also directed to a method for determining an appropriate amount for a human patient using a sustained release oral opioid formulation. The first step of this method consists of administering a unit dose of the once-daily oral sustained release opioid formulation of the present invention described above and in the following sections to a human patient on a daily basis. ing. The method then monitors the pharmacokinetic and pharmacodynamic parameters elicited by the formulation in the human patient, and the pharmacokinetic and / or pharmacodynamic parameters are suitable for repeated treatment of the patient. It includes the following steps of determining whether or not If it is determined that the pharmacokinetic and / or pharmacodynamic parameters are not satisfactory, by administering a unit dose of a sustained release opioid analgesic formulation containing different amounts of opioid analgesic Adjust the dose of opioid analgesic administered to the patient or, if this pharmacokinetic and / or pharmacodynamic parameter is considered appropriate, the dose of opioid analgesic in the unit dose Determine the appropriate dose for the patient by maintaining the previously administered dose. Titration is continued by further adjusting the dose of opioid analgesic until the appropriate steady state pharmacokinetic / pharmacodynamic parameters are achieved in the patient. Thereafter, administration of this dose of opioid analgesic in an oral sustained release formulation is continued on a once daily basis until treatment is complete.

  The term “bioavailability” is defined within the meaning of the present invention as the extent to which a drug (eg an opioid analgesic) is absorbed from a unit dosage.

  The term “sustained release”, within the meaning of the present invention, is maintained in a range where blood (eg, plasma) levels are in the therapeutic range and lower than the toxic level over a period of about 24 hours or more. Defined as the release of a drug (eg, an opioid analgesic) at such a rate.

The term “rapid rate of rise” with respect to opioid plasma concentration is defined within the meaning of the present invention to mean that the formulation exhibits a T _1/2 (abs) of about 1.5 to about 8 hours, ie an absorption half-life. Is done.

The term T _1/2 (abs) is defined within the meaning of the invention as the amount of time required for half of the absorbable opioid dose to travel to the plasma. This value is calculated as a “true” value (taking into account the effects of the disappearance process), not the “apparent” absorption half-life.

  The term “steady state” means that the plasma level of a drug achieves a therapeutically effective minimum or higher level below the minimum plasma toxicity level, and this level is maintained upon subsequent administration of the drug. Means that For opioid analgesics, the minimum therapeutic effect level is determined in part by the amount that pain relief is achieved in the patient. The measurement of pain is extremely subjective and it should be well understood by medical professionals that there can be significant individual differences between patients.

  The terms “maintenance treatment” and “long-term treatment” are defined within the meaning of the present invention as drug treatment administered to a patient after the patient has received an appropriate amount of determination to reach a steady state as defined above for opioid analgesics. Is done.

  Even during steady state administration of opioid analgesics, most patients can be measured or continue to have significant pain. The current state of the art approach to controlled release opioid therapy is to provide a formulation that exhibits zero-order pharmacokinetic amounts upon repeated dosing and minimal maximal to minimal variation in opioid levels. It is. This zero order release gives very slow opioid absorption and a roughly horizontal serum concentration curve over time. A horizontal serum concentration curve is generally convenient, as it provides an effect, but is apparently at a steady state level of effect that minimizes the side effects normally associated with opioid analgesics. It is done. However, it has been found that when sustained release opioids are formulated in this manner, patients often experience a significant degree of discomfort when it is near time to receive the next oral opioid.

  Here, surprisingly, it does not show a substantially horizontal serum concentration curve, but instead gives a more rapid early release of opioids, so that patients who have measurable pain, even if not strong at the time of administration. In many, it has been discovered that a 24-hour oral opioid formulation, which can reach the minimum analgesic concentration more quickly, provides a more rapid and greater analgesic effect. Even with steady-state administration of opioid oral analgesics, it is known that most patients have continued to have measurable or intense pain, so treatment with the novel means of oral opioid treatment disclosed herein. Seems to be extremely effective. Surprisingly, the fact that the method of the present invention provides a more rapid and greater analgesic effect, but the side effects that would normally be expected when higher plasma concentration peaks are seen, is not surprising. It was something that was not predicted.

  It is extremely difficult to define effective plasma levels of opioid (eg, morphine) analgesics. In general, however, for certain opioids, there is a “minimum analgesic concentration” (MEAC) in plasma that does not provide analgesia below it. For example, plasma morphine levels and analgesic effects are indirect, but higher plasma levels generally lead to stronger pain relief. There is a lag time or hysteresis between the peak time of plasma opioid levels and the peak time of drug effect. This is generally the case for pain treatment with opioid analgesics.

  The sustained release once daily formulation of the present invention is characterized by an absorption half-life of about 1 to about 8 hours when the oral sustained release formulation is administered in a fasted state (ie without food). Is characterized by the fact that the plasma concentration of the opioid that is applied is set to show a rapid rate of rise early. In certain embodiments, the absorption half-life is preferably about 1 to about 6 hours, more preferably about 1 to about 3 hours.

It can be said that the formulations of the present invention are further characterized by having a surprisingly fast time to drug peak plasma concentration (ie, t _max ). The _tmax of the sustained release formulation of the present invention can be on the order of about 2 to about 10 hours. In certain preferred embodiments, the t _max provided by these formulations can be on the order of about 4 to about 9 hours.

  Administration of the 24-hour opioid oral sustained release formulation of the present invention results in sedation, respiratory rate, pupil diameter, and / or opioid effects that are continuously answered by the subject after each treatment (ie, oral administration). It is shown that certain drug efficacy points, such as overall scores from questions, are much stronger during the early part of the plasma concentration curve (eg, 4-8 hours after oral administration). Other measures of analgesic effect, such as the sum of pain intensity difference (SPID) and total pain relief (TOTPAR), all gave higher scores and, on the other hand, many In some cases, the associated adverse effects (generally primarily mild or moderate somnolence, nausea and / or dizziness) are also less.

  Opioid analgesic compounds that can be used in the present invention include the following substances: alfentanil, allylprosine, alphaprodine, anileridine, benzyl-morphine ), Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextromoramide, dextromoramide, dextromoramide (di-ampromide), dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, di-methylthiambutene, dioxaohetylbutyrate, dipipanone (dipipanon e), eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydromorphone Hydroxypethidine, isomethadone, ketobemidone, levalorphane, levorphanol, levophenacylmorphane, lofentanil, meperidine, meperidine meptazinol, metazocine, methadone, metopon, morphine, morphine, myrophine, nalbuphine, narceine, nicomorphine, nor-levorphanol ), Normeta (Normethadone), narorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenoxone , Phenomorphan, phenazocine, phenoperidine, piminodine, pyritramide, propheptazine, promedol, properidine, propiram, Propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixtures of mu agonists / antagonists, combinations of mu agonists, and the like . The opioid analgesic may be in the form of a free base, salt, complex or other. In some preferred embodiments, the opioid analgesic is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorhine, any of the foregoing salts, and any mixture thereof.

  In certain preferred embodiments, the sustained release opioid oral dosage form of the present invention contains hydromorphone in an amount of about 4 to about 64 mg of hydromorphone hydrochloride as a therapeutic active ingredient. In another preferred embodiment, the opioid analgesic comprises morphine and the sustained release oral dosage form of the present invention contains from about 5 mg to about 800 mg of morphine. Alternatively, the administration agent may contain the same molar amount of other hydromorphone or morphine salts or bases. In some preferred embodiments in which the opioid is morphine, with a morphine sulfate dose of 30 mg, the maximum plasma concentration is from about 2 ng / ml to about 14 ng / ml, preferably from about 3 ng / ml to about 8 ng / ml. In another preferred embodiment, the opioid analgesic comprises oxycodone and the sustained release oral dosage form of the invention contains from about 5 mg to about 400 mg of oxycodone. In other preferred embodiments, the dosage contains an appropriate amount of other opioid analgesics to provide a substantially equivalent therapeutic effect.

  The sustained release dosage forms of the present invention generally substantially significantly increase the limit and / or extent of concurrent side effects such as nausea, vomiting or sleepiness that are often associated with high blood levels of opioid analgesics. Without reaching the therapeutic level and maintaining it. There is also evidence to suggest that the use of this drug reduces the risk of drug addiction. Further, advantageously, the sustained release dosage form of the present invention releases opioid analgesics at a rate regardless of pH, eg, pH 1.6-7.2. In other words, the dosage form of the present invention avoids “dose dumping” during oral administration.

  In the present invention, an oral opioid analgesic was formulated so as to prolong the analgesic action period in order to enable once-daily use. Surprisingly, these formulations have reduced the degree of adverse effects of the drug at a daily dose that can be compared to conventional immediate release drugs, and while maintaining pain control, Less than the daily dose.

  The retarding substance used in the sustained release formulation of the present invention may be one of those known in the art, such as acrylic polymer, alkyl cellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and any of the foregoing Including, but not limited to, mixtures.

  In some preferred embodiments of the present invention, the sustained release opioid dosage form comprises a plurality of supports comprising the active ingredient, and these supports are coated with a sustained release coating comprising a delayed substance. . The coating agent of the present invention can form a strong, smooth and clean continuous film, can carry colorants and other coating additives, and must be non-toxic, inert and non-tacky .

  The sustained release formulations of the present invention can be used to achieve sustained release of the targeted therapeutic agent, such as heats, long spheres, microspheres, seeds, pellets, ion exchange resin beads, and other multiparticulate systems. It may be used with multiparticulate systems. Beads, granules, spheroids or pellets, etc. prepared according to the present invention can be encapsulated or made into any other suitable unit dosage.

  When the support in the present invention is an inert pharmacological bead, the inert pharmacological bead is about 8 mesh to 50 mesh. In some preferred embodiments, the beads are, for example, nu pariel 18/20 beads.

  In some preferred embodiments of the invention, the sustained release opioid dosage formulation comprises a plurality of supports comprising the active ingredient, and these supports are coated with a sustained release coating comprising a retarder. The coating agent of the present invention can form a strong, smooth and clean continuous film, can carry colorants and other coating additives, and must be non-toxic, inert and non-tacky .

  In order to obtain a sustained release of opioid sufficient to provide an analgesic effect over a long period of time as described in the present invention, the support containing the therapeutic agent is sufficient to increase the weight by about 2 to about 30%. It may be coated with an amount of hydrophobic material. However, the coating is highly dependent on the physical properties of the particular opioid analgesic compound used and the intended release rate.

  In order to obtain a sustained release of opioid sufficient to provide an analgesic effect over a long period of time as described in the present invention, the support containing the therapeutic agent is sufficient to increase the weight by about 2 to about 30%. An amount of retarder may be coated. However, the coating is highly dependent on the physical properties of the particular opioid analgesic compound used and the intended release rate.

  The solvent used for the retarder (which is typically hydrophobic) can be any pharmacologically acceptable solvent including water, methanol, ethanol, methylene chloride and mixtures thereof. However, the coating is preferably based on an aqueous dispersion of a hydrophobic material.

  In some preferred embodiments of the present invention, the hydrophobic polymer comprising a sustained release coating agent is a pharmacologically acceptable acrylic polymer, including but not limited to the following materials; Copolymer of acid and methacrylic acid, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (Methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer and glycidyl methacrylate copolymer.

  In some preferred embodiments, the acrylic polymer comprises one or more of ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters containing a low proportion of quaternary ammonium groups.

  In one preferred embodiment, the acrylic coating agent is an acrylic resin lacquer used in the form of an aqueous dispersion, for example, commercially available from Rohm Pharma under the tradename Eudragit®. In a further preferred embodiment, the acrylic coating agent comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL 30 D and Eudragit® RS 30 D, respectively.

  Eudragit (R) RL 30 D and Eudragit (R) RS 30 D are copolymers of acrylic and methacrylic esters containing a low proportion of quaternary ammonium groups and remain neutral (meth) acrylic esters The molar ratio of ammonium groups to is 1:20 in Eudragit® RL 30 D and 1:40 in Eudragit® RS 30 D. The average molecular weight is approximately 150,000. Abbreviation of abbreviations RL (high permeability) and RS (low permeability) are related to the permeability of these resin agents.

  Eudragit® RL / RS mixture is insoluble in water and digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous and digestive fluids.

  The Eudragit® RL / RS dispersions of the present invention can be mixed in any proportions required to ultimately obtain a sustained release formulation with desirable dissolution characteristics. For example, 100% Eudragit (R) RL, 50% Eudragit (R) RL and 50% Eudragit (R) RS, and 10% Eudragit (R) RL: manufactured from 90% Eudragit (R) RS Delayed coating provides the desired sustained release formulation. Of course, those skilled in the art will recognize that other acrylic polymers may be used, such as Eudragit® L, for example.

  In another preferred embodiment, the hydrophobic polymer that can be used to coat the support of the present invention is a hydrophobic alkylcellulose material such as ethylcellulose. One skilled in the art will recognize that some or all of the ethylcellulose contained in the hydrophobic polymer coating of the present invention may be replaced with other cellulose polymers including other alkylcellulose polymers.

  A commercially available ethylcellulose aqueous dispersion is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving ethyl cellulose in a water-immiscible organic solvent and emulsifying it in water in the presence of a surfactant and a stabilizer. After generating submicron droplets by homogenization, the organic solvent is evaporated in vacuo to form a pseudolatex. In the manufacturing stage, no plasticizer is added to the pseudolatex. Therefore, it is necessary to mix well a suitable plasticizer for Aquacoat® before using it as a coating agent.

  Another aqueous ethylcellulose dispersion is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by adding a plasticizer in the dispersion during the manufacturing process. An aqueous dispersion that can be applied directly on a support by preparing a homogeneous mixture of high-temperature melt of polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) and then diluting with an alkaline solution obtain.

  In embodiments of the invention where the coating agent comprises an aqueous dispersion of a hydrophobic polymer, the inclusion of an effective amount of plasticizer in the aqueous dispersion of hydrophobic polymer further improves the physical properties of the film. Will be. For example, ethylcellulose has a relatively high glass transition temperature and does not form a flexible film under normal coating conditions, so it must be plasticized before it can be used as a coating material. In general, the amount of plasticizer included in the coating solution is based on the concentration of the film former, for example, most commonly from about 1 to about 50% by weight of the film former. However, the concentration of plasticizer can only be accurately determined after careful experimentation with a particular coating solution and application method.

  Examples of suitable plasticizers for ethyl cellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin. However, other water-insoluble plasticizers (acetylated monoglyceride, phthalate ester, castor oil, etc.) can also be used. Triethyl citrate is particularly preferred.

  Examples of suitable plasticizers for the acrylic polymers of the present invention include citrate esters such as triethyl citrate NF XVI, tributyl citrate and dibutyl phthalate, but 1,2-propylene glycol, polyethylene glycol, propylene glycol, Diethyl phthalate, castor oil, and triacetin are also possible. However, other water-insoluble plasticizers (acetylated monoglyceride, phthalate ester, castor oil, etc.) can also be used. Triethyl citrate is particularly preferred.

  The sustained release properties of the formulations of the present invention can be altered, for example, by the following methods; changing the thickness of the hydrophobic coating; changing the specific hydrophobic material used, or eg different acrylic resin lacquers Change the plasticizer addition method (for example, when a sustained release coating is formed from an aqueous dispersion of a hydrophobic polymer); change the ratio of plasticizer to hydrophobic polymer; additional components or additives Inclusion of a dosage form; change manufacturing method; others.

  Opioid-coated, sustained-release globules or beads can be prepared by, for example, dissolving an opioid analgesic in water and then spraying this solution onto a support, such as nu pariel 18/20 beads, using a Wurster insert. Can be prepared. Optionally, other components are also added prior to coating the beads to help the opioid bind to the support and / or to color the solution, etc. For example, a product containing hydroxypropyl methylcellulose or the like, with or without colorant, is added to the solution and the solution is mixed (eg, about 1 hour) before being applied to the beads. The formed coated support, in this example beads, may then optionally be overcoated with a barrier agent to disrupt the therapeutic agent and the hydrophobic sustained release coating. An example of a suitable barrier agent is one comprising hydroxypropyl methylcellulose. However, any film former known in the art may be used. It is desirable that the barrier agent does not affect the dissolution rate of the final product.

  The HPMC protected (optional) opioid beads can then be overcoated with a hydrophobic polymer, preferably containing an effective amount of plasticizer.

  The coating solution of the present invention preferably contains, in addition to a film former, a plasticizer, and a solvent system (ie, water), a colorant for beautification and product discrimination. The dye may be added to the solution of the therapeutic agent rather than to or in addition to the aqueous dispersion of the hydrophobic polymer.

  The aqueous dispersion of the plasticized hydrophobic polymer can be applied by spraying onto a support containing a therapeutic agent using any suitable spraying device known in the art. As a preferred method, a Wurster fluidized bed system is used. In this method, while the acrylic polymer coating agent is sprayed, the core material is fluidized and subjected to a drying action by blowing out air injected from below. In view of the physical properties of the therapeutic agent, the method of incorporation of the plasticizer, etc., a predetermined sustained release of the therapeutic agent is obtained when the coated support is exposed to an aqueous solution, such as gastric juice. A sufficient amount of an aqueous dispersion of hydrophobic polymer is suitably applied. After coating with a hydrophobic polymer, a further overcoat with a film-forming agent such as Opadry® is optionally applied to the beads. This overcoat is done in part to substantially reduce bead aggregation.

  The coated beads are then cured to obtain a stable release rate of the therapeutic agent.

  When the coating agent comprises an aqueous dispersion of ethylcellulose, the coated support is preferably from the glass transition temperature of the coating solution (ie ethylcellulose) as described in US Pat. No. 5,273,760, which is hereby incorporated by reference. At high temperatures and at the cure endpoint, eg, about 60% to about 100% relative humidity until reaching about 60 ° C., and about 48% to about 72 hours at about 60% to about 100% relative humidity. I do.

In a preferred embodiment of the invention aimed at acrylic coatings, the stabilized product is obtained by over-curing the coated support for a required time at a temperature above the Tg of the plasticized acrylic polymer. obtain. At this time, the optimum temperature and time for a particular formulation are determined experimentally. In some embodiments of the present invention, by heat curing at a temperature of about 45 ° C. for about 24 to about 48 hours or longer, as described in US Pat. No. 5,286,493, incorporated herein by reference. A stabilized product is obtained.

Release of the therapeutically active agent from the sustained release formulation of the present invention is further influenced by one or more release modifying agents or by providing one or more routes through the coating. Can do. That is, it can be adjusted to a desired speed. The ratio of the hydrophobic polymer to the water-soluble substance is determined by the required release rate and the solubility characteristics of the selected material, among other factors.

  Release modifiers that function as pore-forming agents may be organic or inorganic and include substances that can be dissolved, extracted or filtered from the coating agent in the environment of use. The pore-forming agent can contain one or more hydrophilic polymers such as hydroxypropylmethylcellulose. The sustained release coatings of the present invention can also include erosion-promoting reagents such as starch and rubber. The sustained release coatings of the present invention are also useful materials for creating microporous flakes in the environment of use, such as polycarbonates containing carbonated linear polyesters in which carbonate groups reappear in the polymer chain. Can also be included. The release modifier can also contain a semipermeable polymer. In certain preferred embodiments, the release modifier is selected from hydroxypropyl methylcellulose, lactose, metal stearate and mixtures thereof. The sustained release coating of the present invention can also include outlet means including at least one passage, orifice or the like. The pathway can be formed by the methods disclosed in US Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all incorporated herein by reference). The path can take any shape such as a circle, triangle, quadrangle, ellipse, and irregular shape.

In another embodiment of the present invention, the present invention can utilize a multiparticulate sustained release matrix. Suitable materials for the sustained release matrix are:
(a) hydrophilic polymers such as rubber, cellulose ethers, acrylic resins and protein-derived materials. Among these polymers, cellulose ethers, particularly hydroxyalkyl cellulose and carboxyalkyl cellulose are preferred. Oral dosage forms may contain 1-80% by weight of at least one hydrophilic or hydrophobic polymer.

(b) fatty acids, glyceryl esters of fatty alcohols, fatty acids, such as mineral and vegetable oils and waxes, digestible, long chain (C ₈ -C _50, especially C ₁₂ -C _40), substituted or unsubstituted hydrocarbon. Hydrocarbons having a melting point of 25-90 ° C are preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form can contain up to 60% (by weight) of at least one digestible long chain hydrocarbon.

  (c) Polyalkylene glycol. The oral dosage form can contain up to 60% by weight of at least one polyalkylene glycol.

For example, a suitable matrix is at least one water soluble hydroxyalkyl cellulose, at least one C ₁₂ -C ₃₆ , preferably C ₁₄ -C ₂₂ aliphatic alcohol, and optionally at least one polyalkylene glycol. Can be included. The at least one hydroxyalkyl cellulose is preferably a hydroxy (C ₁ -C ₆ ) alkyl cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose and especially hydroxyethylcellulose. The amount of at least one hydroxyalkyl cellulose in the oral dosage form will be determined, inter alia, by the precise rate of opioid release required. The at least one aliphatic alcohol can be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certain preferred embodiments, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of at least one fatty alcohol in the oral dosage form will be determined by the exact rate of opioid release required as described above. It will also depend on whether at least one polyalkylene glycol is present or absent in the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably comprises 20-50% by weight of at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, the combined amount of at least one aliphatic alcohol and at least one polyalkylene glycol preferably represents 20-50% by weight of the total dose. Constitute.

  In one embodiment, for example, the ratio of at least one hydroxyalkyl cellulose or acrylic resin to at least one fatty alcohol / polyalkylene glycol determines the release rate of the opioid from the formulation to a significant extent. . The ratio of at least one hydroxyalkyl cellulose to at least one fatty alcohol / polyalkylene glycol is preferably between 1: 2 and 1: 4, particularly preferably between 1: 3 and 1: 4.

  The at least one polyalkylene glycol can be, for example, polypropylene glycol or preferably polyethylene glycol. The average molecular weight of the at least one polyalkylene glycol is preferably 1000 to 15000, in particular 1500 to 12000.

Another suitable sustained release matrix would contain alkyl cellulose (especially ethyl cellulose), C ₁₂ -C ₃₆ aliphatic alcohol and optionally polyalkylene glycol.

  In addition to the above ingredients, the sustained release matrix may contain other materials in appropriate amounts, such as diluents, lubricants, binders, granulation aids, colorants, flavors commonly used in the pharmaceutical field. Agents and glidants can also be included.

These sustained release matrices can be made, for example, by:
(a) forming granules containing at least one water-soluble hydroxyalkylcellulose and an opioid or opioid salt;
(b) mixing the hydroxyalkyl cellulose containing granules with at least one C ₁₂ -C ₃₆ aliphatic alcohol; and
(c) Optionally compress and form granules. Preferably, the hydroxyalkyl cellulose / opioid using water is granulated by wet granulation. The amount of water added during the wet granulation step can be, for example, 1.5 to 5 times, especially 1.75 to 3.5 times the dry weight of the opioid.

  In yet another alternative embodiment, the spheronizing agent can be spheronized with the active ingredient to form a spheroid. Although fine hydrous lactose is preferably used in a morphine sulfate sustained release preparation produced by a powder layering technique, microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (registered trademark, FMC Corporation). In such embodiments, in addition to the active ingredient and spheronizing reagent, the spheroid can also contain a binder. Suitable binders such as low viscosity water soluble polymers will be known to those skilled in the pharmaceutical arts. However, a water soluble hydroxy lower alkyl cellulose such as hydroxypropyl cellulose is preferred. In addition (or alternatively), the spheroid can comprise a water-insoluble polymer, particularly an acrylic polymer, an acrylic copolymer, such as a water-insoluble polymer, ethyl methacrylate acrylate copolymer or ethyl cellulose. In such embodiments, the sustained release coating agent generally comprises a water insoluble material such as (a) a wax, alone or mixed with a fatty alcohol; or (b) shellac or zein. Would include.

  The substrate of the present invention can also be produced by melt granulation techniques. In such a situation, the finely divided form of the opioid is combined with a binder (which is also in particulate form) and any other inert ingredients, and then the mixture is mechanically pelletized (e.g. in a high shear mixer). The mixture is made spherical by forming granules, spheres). The pellets (granules, spheres) can then be sieved to obtain pellets of the required size. The binding material is preferably in particulate form and has a melting point of about 40 ° C. or higher. Suitable binding substances include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides and the like.

  In certain preferred embodiments of the invention, an effective amount of opioid in immediate release form is included in the administered 24-hour sustained release single dose opioid formulation. The immediate release form of the opioid includes an amount effective to reduce the time to reach the maximum concentration of opioid in blood (eg, plasma). In such embodiments, the substrate of the present invention can be coated with an effective amount of the opioid in immediate release form. For example, if the sustained opioid release from the formulation is due to a controlled release coating, the immediate release layer will overcoat the surface of the controlled release coating. On the other hand, an immediate release layer can be coated on the surface of a substrate where the opioid is incorporated into a controlled release matrix. If multiple sustained release substrates containing an effective single dose of opioid (for example, multiparticulate systems including pellets, spheres, beads, etc.) are incorporated into hard gelatin capsules, the immediate release portion of the opioid dose can be By incorporating a sufficient amount of immediate release opioid as an internal powder or granule, it can be incorporated into gelatin capsules. Alternatively, the gelatin capsule itself can be coated with an immediate release layer of opioid. Those skilled in the art will also be aware of other alternatives that incorporate an immediate release portion of the opioid into a single dose. Such alternatives are considered to be encompassed by the appended claims. It has been found that inclusion of such an effective amount of immediate release opioid in a single dose significantly reduces the patient's relatively high distress experience.

The dosage form can be prepared by preparing a dosage form consistent with any of the methods described above, or by other methods known to those skilled in the pharmaceutical arts. In addition to the above, sustained release opioid formulations can also be manufactured as tablets. In such instances, the tablets may be in addition to opioids and retarders, as well as other materials in appropriate amounts commonly used in the pharmaceutical field, such as diluents, lubricants, binders, granulation aids, colorings. Agents, flavorings and glidants can optionally be included in amounts up to about 50% by weight of the microparticles. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in H andbook of Pharmaceutical Excipients , American Pharmaceutical Association (1986). And is hereby incorporated by reference. Techniques and compositions for making solid oral dosage forms, formulations histological dosage forms: Tablets (Pharmaceutical Dosage Forms: Tablets) ( Lieberman, Lachman and Schwartz, editors) Second Edition, published by Marcel Delker, described Inc. Which is hereby incorporated by reference. Tablets (compressed and molded), capsules (hard and soft gelatin) and techniques for the production of pills and also Remington of pharmaceutics Science (Remington's Pharmaceutical Science) composition (Arthur Osol, editor), 1553-1593 (1980 ) And is hereby incorporated by reference.

  In order to titrate a human patient with the sustained release opioid formulation of the present invention, multiple blood samples are taken from the patient over the course of the dosing interval. The samples thus obtained are then tested to determine the plasma levels of opioid analgesics and their active metabolites. The values obtained in this way can then be used to measure other pharmacokinetic parameters. Determining whether a patient has a sufficient medicinal response in the above dosage form includes, for example, reference to pre-measured blood values, results of subjective pain tests given to the patient, profile of patient side effects, etc. Will be made. Thereafter, it can be determined whether it is necessary to adjust the dose higher or lower.

  Administration of the sustained release unit formulation is continued at a single dose interval to maintain a sufficient pharmacologic response with the sustained release formulation. Preferably, a sufficient pharmacologic response will last from about 12 to about 24 hours, most preferably about 24 hours or more.

  Administration of the sustained release unit formulation is continued at a single dose interval to maintain the sufficient pharmacologic response with the sustained release formulation.

  If necessary, the above steps are repeated until sufficient drug response is measured by the sustained release unit dosage form.

  According to the method described above, the patient's titration can be measured using a sustained release opioid analgesic formulation. Subsequent maintenance treatment can be provided using similar sustained release formulations.

  The following examples illustrate various aspects of the present invention. It is not intended to limit the scope of the claims in any way.

Examples 1-2
In Example 1, 5% W / W sustained release coating morphine sulfate sustained release beads containing Eudragit® RS were prepared with a 10% immediate release morphine sulfate overcoat. In Example 2, 8% W / W sustained release coating morphine sulfate sustained release beads containing Eudragit® RS were prepared with a 10% immediate release morphine sulfate overcoat.

  Morphine sulfate beads were first manufactured using rotor processing technology. The formulation of morphine sulfate beads with a sustained release coating is shown in Table 1 below.

  A sustained release coating was then applied to the morphine sulfate beads. The sustained release coating formulations of Examples 1 and 2 are shown in Table 2 below.

  A sustained release coating was prepared as follows. Eudragit RS30D was plasticized with triethyl citrate and talc for about 30 minutes. A large amount of morphine sulfate beads were loaded into a Glatta Wurster Insert equipped with a 1.2 mm spray nozzle, and the beads were coated in Examples 1 and 2 to 5% and 8% weight gain, respectively. A final protective Opadry dispersion overcoat was then applied in the Wurster Insert. After completion, the beads were cured for 2 days in a 45 ° C. drying oven. The hardened beads were then filled into gelatin capsules with a strength of 30 mg.

  Dissolution testing was performed on gelatin capsules with the U.S.P. apparatus (Apparatus II) (Paddle method). Capsules were placed in 700 ml of similar gastric fluid (without enzyme) at 100 rpm 37 ° C. for the first hour and in 900 ml of similar gastric fluid (without enzyme) after the first hour. The results of the percentage of dissolved morphine sulfate over time in Examples 1 and 2 are shown in Table 3 below:

Clinical evaluation of Examples 1-2
Ten normal healthy male subjects were enrolled in four randomized, single-dose, crossover pharmacokinetic / pharmacodynamic studies with the same product and morphine CR 30 mg tablets (MS Contin In comparison with (R), the effect of food on the pharmacokinetic / pharmacodynamic profile of Example 1 was characterized using plasma morphine concentrations and pharmacodynamic parameters, each in the fasted state. . A comparison of Example 2 with a morphine controlled release 30 mg tablet (MS Contin®) was also performed. Plasma morphine concentrations were used to calculate pharmacokinetic parameters including: (a) absorption and elimination rates; (b) area under the curve (AUC); (C) maximum plasma concentration (C _max ); (d ) Time to maximum plasma concentration (T _max ); (e) T _1/2 (disappearance). The pharmacodynamic effects compared to plasma concentrations of morphine are described from data obtained from the following pharmacodynamic parameters: physiological mood, sedation, respiratory rate, pupil measurement and indirect questionnaire.
Clinical experimental evaluation Blood samples were analyzed for hematology (hemoglobin, hematocrit, red blood cell count, differential white blood cell count, platelet count) and blood chemistry analysis (calcium, inorganic phosphate, uric acid, total protein, albumin, cholesterol, alkaline phosphatase, lactate dehydrogenase) (LDH), total bilirubin, serum glutamate-oxaloacetate transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), fasting blood glucose, blood urea nitrogen (BUN), serum creatine pre- and post-test (72 hours) (Ie, 72 hours after Phase 4 dosing) Urine samples were collected from urinalysis (specific gravity, glucose, albumin, bile, pH, acetone, microscopic examination, pre- and post-hoc (72 hours) studies ( (Ie 72 hours after Phase 4 dosing)
Collected for. Preliminary test urinalysis for forbidden drugs was performed during the screening process and immediately prior to administration of each dose of the drug (Day 1 through Phase 4).

Plasma morphine concentration was measured immediately before dosing (0 hour) and then after each dosing 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 6, 8, 10, 12, 18, 24, 36, 48 and It was measured from a blood sample collected 72 hours later. About 10 ml of each blood sample was placed in a tube containing ethylenediaminetetraacetic acid (EDTA) solution, an anticoagulant. After centrifugation, the plasma was dispensed into two 5 ml labeled polypropylene tubes and frozen at -20 ° C. One of the samples was transported to a designated analytical laboratory in dry ice sufficient to keep frozen for 2 days, and the other was kept frozen at the laboratory site as a reserve.
Pharmacodynamic measurement Based on the measurement of the following pharmacodynamic parameters, immediately before blood collection (within 30 minutes before dosing) and thereafter 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8 of each dosing , 10, 12, 18, 24, 36, 48 and 72 hours later.

  Physiological mood (measured by visual analog scale (VAS) of subject diary)-10 minutes before blood collection. The VAS has one end set to Worst Mood and the other end set to Best Mood.

  Sedation (measured by VAS on subject diary)-10 minutes before blood collection. VAS set one end to Asleep and the other to Awake.

Respiration rate (breathing per minute)-Within 5 minutes of blood collection. (Data was recorded in subject diary)
Pupil diameter-measured by pupillometer-within 5 minutes of blood collection. Only the left eye was measured during the whole period. (Data was recorded in subject diary)
FIG. 1 is a graph showing an average sedation curve with respect to time in Example 1 (fasting). FIG. 2 is a graph showing an average sedation curve with respect to time in Example 2 (fasting). FIG. 3 is a graph showing an average respiration rate curve with respect to time in Example 1 (fasting). FIG. 4 is a graph showing an average respiration rate curve with respect to time in Example 2 (fasting).

Plasma morphine concentration was measured by high performance liquid chromatography. The arithmetic mean C _max , T _max , AUC, half-life and oral bioavailability calculated from plasma morphine concentrations for each time are shown in Tables 4 and 5 below:

* Statistically significant compared to MS Contin® (p <.0500) (based on unconverted data)
F ₀ (%) = Oral Bioavailability (Study Drug Least Squares Mean / Control Least Squares Mean)
Table 6 provides the mean (± SD) plasma morphine concentration (ng / ml) after dosing of MS Contin® and Examples 1 and 2.

  Table 7 provides the mean (± S.D.) Pharmacokinetic parameters after dosing for MS Contin® and Examples 1-2.

When Example 1 (fasted) and MS Contin (registered trademark) (fasted) were compared, a statistically significant difference in C _max was observed. There was no statistically significant difference between the two treatments at T _max , AUC (0,72), AUC (0,00) and T _1/2 (elim) or T _1/2 (abs). The 90% confidence intervals for all pharmacokinetic parameters were outside the 80-120% confidence limits.

When Example 1 (Fed) and MS Contin® (Fast) were compared, there was a statistically significant difference in C _max . There were no statistically significant differences between the two treatments at T _max , AUC (0,72), AUC (0,00) and T _1/2 (elim) or T _1/2 (abs). The 90% confidence intervals for all pharmacokinetic parameters were outside the 80-120% confidence limits.

When comparing the fed state and the fasted state of Example 1, C _max , T _max , AUC (0,72), AUC (0,00) and T _1/2 (elim) or T _1/2 (abs) There was no statistically significant difference in. The 90% confidence intervals for all pharmacokinetic parameters were outside the 80-120% confidence limits.

The effect of feeding on the absorption of Example 1 is characterized by higher C _max and extended T _max and T _1/2 (abs) values. However, the extent of absorption (based on AUC) differed by less than 3% in the fasted and fed states.

When comparing Example 2 (fasted) to MS Contin® (fasted), it was statistically determined to be C _max , T _max , AUC (0,72), AUC (0,00) and T _1/2 (elim) A significant difference was observed. There was no statistically significant difference in T _1/2 (abs) between the two treatments. The 90% confidence intervals for all pharmacokinetic parameters were outside the 80-120% confidence limits.

Based on the 90% confidence interval analysis, neither the Example 1 nor the Example 2 beads in the fasted or fed state were comparable to MS Contin® tablets. However, none of the experimental controlled-release morphine formulations were bioequivalent to MS Contin® tablets, both of which had relatively low C _max and extended T _max and apparent T _1/2 (elim) value provided.

Linear regression of each pharmacodynamic parameter versus log-converted concentration for each subject and treatment resulted in 48 regressions (48/240; 20%) out of 240 with R ² values of 20% or more, of which 8 (8 / 240; 3%) had a value of 50% or more. When analyzed by treatment alone, all R ² values were less than 10%. These values did not indicate a significant linear relationship between pharmacodynamic measurements and log concentrations.

  Examination of the mean hysteresis curve suggested a possible relationship between pupil diameter and morphine concentration. In MS Contin® and Example 1, the pupil diameter tended to decrease as morphine concentration increased and then tended to increase as morphine concentration decreased. FIG. 5 is a graph showing a curve of average pupil diameter with respect to time in Example 1 (fasted). FIG. 6 is a graph showing a curve of the average pupil diameter with respect to the time in Example 2 (fasting). No relationship was found between morphine concentration and any other parameters.

Two subjects (20%) reported 6 side effects during the administration of MS Contin®. Three subjects (30%) reported 6 side effects during administration of controlled release morphine beads (Example 1; fasting). One side effect was reported by one subject in each of the following treatment groups: Example 1 (Fed) and Example 2 (Fast). There were no clinically significant changes in the measurement of physical examination or EKG results, clinical laboratory values or vital signs during the study.

The revised questionnaire on specific drug action is Jasinski, DR (1977) Assessment of the Abuse Potential of Morphine-Like Drugs (Methods) in Drug Addiction I (Martin, WR) pp. 197-258, Springer-Verlag, New York. Used in Man) [Evaluation of abuse of morphine-like drugs (method for human use)] and Preston, KL, Jasinski, DR and Testa, M. (1991) Abuse Potential and in Drug and Alcohol Dependence 27: 7-17 The questionnaire adopted in the Pharmacological Comparison of Tramadol and Morphine was amended. This questionnaire consisted of 10 items evaluated by the subject and the observer. These items were related to opiate-agonist drug symptoms and were as follows:
Questions to subjects 1. Do you feel any action of the drug?
2. Is itchy skin?
3. Are you relaxed?
4). Are you sleepy?
5). Are you drunk?
6). Are you nervous?
7). Are you full of energy?
8). Want to talk?
9. Do you have nausea?
10. Do you feel dizzy?
The subject answered each question by marking vertically along a 100-mm VAS secured with “none at all” on one end and “very” on the other end.
Questions to the observer Does the subject show any drug action?
2. Is the subject scratching their skin?
3. Is the subject relaxing?
4). Is the subject drunk?
5). Is the subject nervous?
6). Is the subject talking?
7). Is the subject vomiting?
8). Is the subject confused?
9. Is the subject resting?
10. Is the subject sweating?
The observer answered each question by marking it vertically along a 100-mm VAS that was fixed with “none at all” and “very” at the other end. FIG. 7 is a graph showing the average subject questionnaire vs. time curve for Example 1 (fasting). FIG. 8 is a graphical representation of the average subject questionnaire versus time curve for Example 2 (fasting).

To record the side effects experience experience of direct questions were induced or spontaneously reported during side-effects, if it is tolerated, consider immediately main was the researchers, the severity, duration and neutralization measures Decided to start. Subjects were to be monitored until they returned to baseline.
Analyzes Plasma morphine was analyzed using high performance liquid chromatography (HPLC). The measurement limit was 0.5 ng / mL. Appendix V contains an analytical record of plasma morphine.

Statistical and pharmacometric methods Parameters Continuous plasma morphine values collected from each subject and treatment were corrected for zero time values by subtracting zero time values from all values in the series.

  Continuous data sets with zero time values exceeding the minimum assay sensitivity were considered unacceptable for data analysis as described above. Using the plasma concentrations with baseline correction, the following parameters were estimated for each subject and treatment.

C _max (ng / ml) —maximum observed plasma morphine value;
T _max (hours) —the time of occurrence of C _max with respect to dosing time;
T _1/2 (elim; hours) −
T _1/2 elim) -0.693 / K _e
[Where K _e is SAS Release 6.07 (SAS Institute, Cary , NC)
The apparent half-life of plasma morphine excretion calculated according to PROC NLIN.
T _1/2 (abs; hours) −
_{T 1/2 (abs) -0.693 / K} a
Apparent half-life of absorption calculated according to

  FIG. 9 shows the mean plasma morphine concentration-time profile obtained by the comparative example (MS Contin 30 mg) (fasted) when compared to the capsules of Example 1 (fasted, fasted) and Example 2 (fasted). It is represented by a graph.

From the above results, it can be seen that the preparation of Example 1 reaches a higher C _max earlier than the preparation of Example 2, but the absorption of morphine is slightly lower. From a visual review of time-effect data regarding sedation, respiratory rate, pupil size, and the sum of questionnaire scores recorded by the subject consecutively after each treatment, an early time-effect curve (e.g., 4- It is clear that the intensity of each pharmacodynamic endpoint at 8 hours) is greater.

Example 3
Beads with a relatively high load of morphine sulfate were produced on a Glatt Rotor Processor using the powder overlay method. The high load bead formulation is shown in Table 8 below.

  The sustained release coating included an acrylic polymer (ie, Eudragit® RL). To further enhance the stability, an HPMC protective coat was also added between the Eudragit layer and the morphine immediate release layer. The formulation for the sustained release coating of Example 3 is shown in Table 9 below.

  The sustained release coating and the immediate release coating were coated as follows. Eudragit RL 30D was plasticized with triethyl citrate and talc for about 30 minutes. A single dose of morphine sulfate beads was placed in a Glatt Wurster Insert equipped with a 1.2 mm spray nozzle and coated with a 5% weight gain. The final protective Opadry dispersion overcoat was then applied with a Wurster Insert. Upon completion, the beads were cured for 2 days in a 45 ° C. drying oven. The hardened beads were then filled into gelatin capsules with a content of 30 mg.

  These capsules were then subjected to a dissolution test. Dissolution testing was performed on the finished product using USP Apparatus II (Paddle method). The capsules were placed in 700 ml of simulated gastric fluid (without enzyme) at 100 rpm and 37 ° C. for the first hour and then in 900 ml of simulated intestinal fluid (without enzyme). The results of the dissolution test are shown in Table 10 below.

Clinical Evaluation of Example 3 Thirteen normal healthy male subjects examined the effects of food on the pharmacokinetics and pharmacodynamics of the 30 mg dose (capsule) of Example 3 per dose, randomized Registered for open label experiments. The pharmacokinetic and pharmacodynamic results of sustained release formulations in these fed and fasted subjects were also compared to the results of MS Contin® 30 mg tablets in fasted subjects. Plasma morphine concentrations were used to calculate the following pharmacokinetic parameters: (a) apparent absorption and excretion rates, (b) area-under-the-curve (AUC), (c) maximal plasma Concentration (C _max ), (d) Time for maximum plasma concentration (T _max ), (e) T _1/2 (abs) and (f) T _1/2 (elim). Pharmacodynamic effects were determined by mood, sedation, respiratory rate, pupillary measurements and evaluation of subject's accompanying questionnaires.

Plasma morphine concentration was measured by high performance liquid chromatography. All subjects completed this experiment and participated in biopharmaceutical analysis. Arithmetic mean C _max , T _max , AUC, half-life, and oral bioavailability data calculated from individual plasma morphine concentrations-time are shown in Tables 11 and 12 below.

  Table 13 shows the mean (± SD) plasma morphine concentration (ng / ml) after administration of MS Contin® and Example 3.

  Table 14 shows the mean (± SD) pharmacokinetic parameters after administration of MS Contin® and Example 3.

The ratio of mean AUC by least squares of the 30 mg capsule of Example 3 administered under fed and fasted conditions indicates that the AUC value under fed conditions is within ± 20% of the AUC value under fasted conditions . The C _max value was 64% greater under fed conditions. The value of T _max under fed conditions was approximately 50% when administered under fasted conditions. The apparent absorption rate is about 35% greater under fed conditions, and the apparent excretion rate under fed conditions is about 35% of that under fasted conditions, indicating that morphine absorption is slowed by the presence of food, It shows that the discharge speed increases.

The ratio of the mean AUC of the 30 mg capsule of Example 3 and the MS Contin® 30 mg tablet by the least squares method is that the AUC (0,72) value of Example 3 is ± 20% of that of MS Contin®. It indicates that the AUC (0.00) value is 44% larger in the case of Example 3. The C _max value of Example 3 was 29.5% of that of MS Contin®. The value of T _max under the feeding conditions was more than 5 times that of Example 3. The apparent absorption rate of Example 3 is about 91% greater, and the apparent discharge rate of Example 3 is more than 16 times that of MS Contin®, indicating that the absorption and excretion of morphine is that of Example 3. Shows slower in some cases.

From the results of linear regression of each pharmacodynamic parameter versus log-transformed concentration for each subject and treatment, 74 out of 315 regressions (24%) had an R ² value greater than 20% and 12 out of 315 ( 4%) had a value of 50% or more. When analyzed by treatment alone, R ² values higher than 10% were zero. For each R ² value of 20% or more, it was found in 21 (33%) of 63 regressions of the subject's MSDEQ [Modified Specific Drug Effect Questionnaire] score for log concentration, and 63 Of these, 7 (11%) was 50% or more. These values show a possible linear relationship between log concentration and the subject's MSDEQ score. The relationship between the morphine concentration and the subject's MSDEQ score is also apparent from an examination of the mean hysteresis curve. For each formulation, the subject's MSDEQ score tended to increase with increasing morphine concentration and then decreased with decreasing morphine concentration. No relationship was observed between morphine concentration and other pharmacodynamic parameters.

FIG. 10 is a graphical representation of the average morphine concentration-time profile obtained by the comparative example (MS Contin 30 mg) (fasted) when compared to the capsules of Example 3 (fed, fasted). FIG. 11 graphically represents the average sedation versus time curve for Example 3 (fasting). FIG. 12 is a graph showing the average respiration rate versus time curve for Example 3 (fasting). FIG. 13 is a graph showing the average pupil size versus time curve for Example 3 (fasting). FIG. 14 is a graph showing the mean subject MSDEQ versus time curve for Example 2 (fasted).

Example 4
Beads with a relatively high load of morphine sulfate were produced on a Glatt Rotor Processor using the powder overlay method. The high load bead formulation is shown in Table 15 below.

  These immediate release substrate beads were produced on a Glatt Rotor Processor using a powder overlay method.

  The sustained release coating included an ethylcellulose acrylic polymer (ie Aquacoat ECD 30). To further increase stability, an HPMC protective coat was also included after the Aquacoat layer. The formulation for the sustained release coating of Example 4 is shown in Table 16 below.

  The sustained release coating and final overcoat were coated as follows. A mixture of Aquacoat ECD 30 and Methocel E5 Premium was plasticized with triethyl citrate for about 30 minutes. A single dose of morphine sulfate beads was placed in a Glatt Wurster Insert equipped with a 1.2 mm spray nozzle and coated to a weight gain of 25%. Upon completion of the delayed coating, the beads were cured for 3 days in a 60 ° C./80% RH temperature / humidity chamber. Thereafter, the cured beads were dried in a drying oven at 60 ° C. for 1 day. The dried cured beads were placed in a Glatt Wurster Insert equipped with a 1.2 mm spray nozzle and a final protective Opadry dispersion overcoat was applied. The completed sustained release beads were individually filled into the same gelatin capsules at a total content of 60 mg with low load immediate release morphine sulfate beads. The sustained release beads accounted for 90% or 54 mg capsule content and the immediate release beads accounted for 10% or 6 mg capsule content.

  These capsules were then subjected to a dissolution test. Dissolution testing was performed on the finished product using USP Apparatus II (Paddle method). The capsules were placed in 700 ml of simulated gastric fluid (without enzyme) at 100 rpm and 37 ° C. for the first hour and then in 900 ml of simulated intestinal fluid (without enzyme). The results of the dissolution test are shown in Table 17 below.

Example 5
Beads with a relatively high load of morphine sulfate were produced on a Glatt Rotor Processor using the powder overlay method. The high load bead formulation is shown in Table 18 below.

  The sustained release coating included an acrylic polymer (ie, Eudragit® RS / RL). An HPMC protective coating was also included after the Eudragit layer to further increase stability. The formulation of the sustained release coating of Example 5 is shown in Table 18 below.

  The sustained release coating and the final coating were coated as follows. Eudragit RS / RL 30D was plasticized with triethyl citrate and talc for about 30 minutes. A single dose of morphine sulfate beads was placed in a Glatt Wurster Insert equipped with a 1.2 mm spray nozzle and coated with a 5% weight gain. The final protective Opadry dispersion overcoat was then applied with a Wurster Insert. Upon completion, the beads were cured for 2 days in a 45 ° C. drying oven. The hardened beads were then filled into gelatin capsules at a content of 60 mg.

  These capsules were then subjected to a dissolution test. Dissolution testing was performed on the finished product using USP Apparatus II (Paddle method). The capsules were placed in 700 ml of simulated gastric fluid (without enzyme) at 100 rpm and 37 ° C. for the first hour and then in 900 ml of simulated intestinal fluid (without enzyme). The results of the dissolution test are shown in Table 19 below.

Example 6
Matrix beads Matrix beads with a relatively high load of morphine sulfate were produced on a Glatt Rotor Processor using the powder overlay method. The formula for the high load matrix beads is shown in Table 20 below.

  The matrix component contained ethylcellulose polymer (ie Aquacoat ECD 30). To further increase stability, an HPMC protective coat was also included after the Aquacoat layer.

  Matrix beads were produced as follows. Aquacoat ECD 30 was plasticized with tributyl citrate for about 30 minutes. Morphine sulfate powder and lactose were blended in a Hobart mixer for about 5 minutes. A single dose of sugar beads was placed in a Glatt rotor insert equipped with a 1.2 mm spray nozzle / powder feed assembly. A precision powder feeder was placed over the spray nozzle / powder feeder assembly and charged with the morphine sulfate / lactose blend. The sugar beads were then overlaid with a morphine sulfate / lactose blend using a plasticized hydrophobic polymer dispersion (ie Aquacoat ECD 30 and tributyl citrate) as a binder. After completion of the overlay process, a final protective Opadry dispersion overcoat was applied. Next, the beads were cured for 1 day in a 60 ° C. drying oven. Finally, hardened beads were filled into gelatin capsules with a content of 60 mg.

  These capsules were then subjected to a dissolution test. Dissolution testing was performed on the finished product using USP Apparatus II (Paddle method). The capsules were placed in 700 ml of simulated gastric fluid (without enzyme) at 100 rpm and 37 ° C. for the first hour and then in 900 ml of simulated intestinal fluid (without enzyme). The results of the dissolution test are shown in Table 21 below.

Clinical evaluation of Examples 4, 5 and 6 14 normal healthy human subjects affect the single dose pharmacokinetics and pharmacodynamics of Examples 1, 2 or 3 in the presence or absence of food Enrolled in 6 different crossover, randomized, and open-label experiments. Plasma samples were analyzed for morphine concentrations and the following pharmacokinetic results were calculated. The results are shown in Table 22 below.

Example 7
8 mg once daily capsule of hydromorphone hydrochloride
In preparing drug-loaded hydromorphone beads, hydromorphone hydrochloride was dissolved in water, Opadry Y-5-1442 was added, and mixed for about 1 hour to obtain a 20 w / w% suspension. This suspension was then sprayed onto Nu-Pareil 18/20 mesh beads using a Wurster insert.

The first overcoat hydromorphone loaded beads were coated with a 5 w / w% increase in Opadry Light Pink using a Wurster insert. This overcoat was applied as a protective coating.

After coating the first overcoat of the delay coat , the hydromorphone beads were coated with a 5 wt% increase in the delay coating mixture of Eudragit RS 30D and Eudragit RL 30D (RS vs. RL, 90:10). Eudragit suspension was also added with triethyl citrate (plasticizer) and talc (anti-sticking agent). This coating suspension was applied using a Wurster insert.

When coating of the second overcoat retarded coating was complete, the hydromorphone beads were coated with a final overcoat of Opadry Light Pink using a Wurster insert to a 5% weight gain. This overcoat was also applied as a protective coating.

After coating the cured final overcoat, the hydromorphone beads were cured in an oven at 45 ° C. for 2 days.

The encapsulated beads were manually filled into size # 2 clear gelatin capsules with an 8 mg content of hydromorphone hydrochloride.

  The formulation of Example 7 is shown in Table 23 below.

Dissolution Test The above capsules were tested using USP methodology and were found to have the following results:

Time start
1 hour 17.2
2 hours 48.4
4 hours 77.4
8 hours 93.3
12 hours 97.2
18 hours 98.8
24 hours 98.8

A single dose randomized, crossover bioavailability experiment was performed using the 8 mg controlled release hydromorphone hydrochloride capsule described above and two immediate release 4 mg tablets (Dilaudid®) as controls. Conducted under food and fasting conditions. Blood samples were examined for hydromorphone concentrations and the following pharmacokinetic parameters were calculated. The results are shown in Table 24 below.

  The above-described embodiments are not meant to be exclusive. Many other modifications of the invention will be apparent to those skilled in the art and are intended to be within the scope of the claims.

The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.

FIG. 1 illustrates the time versus average sedation curve of Example 1 (fasting). FIG. 2 illustrates the time versus average sedation curve of Example 2 (fasting). FIG. 3 illustrates the time versus average respiration rate curve of Example 1 (fasted). FIG. 4 illustrates the time versus average respiration rate curve of Example 2 (fasting). FIG. 5 illustrates the time versus average pupil diameter curve for Example 1 (fasted). FIG. 6 illustrates the time versus average pupil diameter curve for Example 2 (fasted). FIG. 7 illustrates the time versus average subject question curve for Example 1 (fasted). FIG. 8 illustrates the time versus average subject question curve for Example 2 (fasting). FIG. 9 shows the time versus mean plasma morphine obtained using the comparative example (MS Contin 30 mg) (fasted) compared to the capsules of Example 1 (Fed and fasted) and Example 2 (Fasted). A density curve is illustrated. FIG. 10 illustrates the time versus mean plasma morphine concentration curve obtained using the comparative example (MS Contin 30 mg) (fasted) compared to the capsule of Example 3 (fed and fasted). is there. FIG. 11 illustrates the time versus average sedation curve for Example 3 (fasting). FIG. 12 illustrates the time versus average respiration rate curve of Example 3 (fasting). FIG. 13 illustrates the time versus average pupil diameter curve for Example 3 (fasting). FIG. 14 illustrates the interrogation curve for the modified special drug effect of Example 2 (fasted) versus the average subject.

Claims (14)

An oral sustained release formulation containing a pharmaceutically effective amount of morphine, a salt thereof, or a mixture thereof coated on a plurality of inert beads,
Each coated bead
(i) a portion of said effective amount of morphine coated on inert beads and hydroxypropyl methylcellulose ;
(ii) a retarding material coating covering morphine and hydroxypropylmethylcellulose coated on said inert beads, comprising a pharmaceutically acceptable acrylic polymer, a mixture of pharmaceutically acceptable acrylic polymers, a cellulose material, and a cellulose material A retarder coating containing a hydrophobic polymer selected from the group consisting of:
(iii) an overcoat covering the retarder coating, the overcoat comprising a further portion of the effective amount of morphine and hydroxypropyl methylcellulose ;
Wherein the preparation is when 1 clothing administered to a human patient, to provide an initial rate of rise in 2 4 hours or more over a effective analgesic treatment and the plasma concentration of the morphine, the initial rate of rise, (a) 4 maximum plasma concentration arrival time of morphine within the time to 9 hours (Tmax), and (b) characterized by the absorption half-life of 1 hour to 6 hours rather based on the administration to a patient in a fasted state, the formulation.   The sustained release formulation of claim 1, wherein the formulation provides an absorption half-life of 1 hour. The sustained release formulation of claim 1, wherein the formulation provides an absorption half-life of 1 hour to 3 hours. 4. The sustained release formulation of any one of claims 1 to 3, wherein the maximum plasma concentration of morphine is 2 to 14 ng / ml based on a 30 mg dose of morphine sulfate. Maximum plasma concentration of the morphine, based on the morphine sulfate 30mg dose, 3 is ~8ng / ml, sustained-release preparation according to any one of claims 1 to 3. The sustained-release preparation according to any one of claims 1 to 3, wherein the pharmaceutically effective amount of morphine is 5 to 800 mg of morphine. 7. A sustained release formulation according to any one of claims 1 to 6, which results in a maximum in vivo plasma concentration of the morphine 4 hours after administration. Each of the coated beads is 0 . The sustained-release preparation according to any one of claims 1 to 7, having a diameter of 5 to 2 mm.   9. The sustained release formulation according to any one of claims 1 to 8, wherein a portion of the morphine dose contained in the overcoat is in an immediate release form.   The sustained release formulation of claim 1, wherein the mixture of pharmaceutically acceptable acrylic polymers is a mixture of two pH independent acrylic polymers. A method for preparing an oral sustained release opioid formulation for once daily administration comprising a pharmaceutically effective amount of morphine, a salt thereof, or a mixture thereof coated on a plurality of pharmaceutically acceptable beads, comprising: The method is
(a) coating inert beads with a portion of the effective amount of morphine and hydroxypropyl methylcellulose ;
(b) a hydrophobic polymer selected from the group consisting of a pharmaceutically acceptable acrylic polymer, a mixture of pharmaceutically acceptable acrylic polymers, a cellulose material, and a mixture of cellulose materials on the coated inert beads. Overcoating a retarder coating containing; and
(c) overcoating the delayed substance coated beads with an overcoat containing a further portion of the effective amount of morphine and hydroxypropyl methylcellulose ;
Wherein the preparation is when 1 clothing administered to a human patient, to provide an initial rate of rise in 2 4 hours or more over a effective analgesic treatment and the plasma concentration of the morphine, the initial rate of rise, (i) fasted absorption half-life of 1 hour to 6 hours rather based on the administration of state to the patient, and (ii) characterized by 4 hours to 9 morphine peak plasma concentration arrival time within hours (Tmax), the method. 12. The method of claim 11, wherein the oral sustained release formulation exhibits an absorption half-life of 1 hour. 12. The method of claim 11, wherein the oral sustained release formulation exhibits an absorption half-life of 1 hour to 3 hours.   12. The method of claim 11, wherein a portion of the morphine dose contained in the overcoat is in an immediate release form.

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